HER2-independent antitumor and pharmacodynamic responses to trastuzumab deruxtecan in patients with advanced solid tumors.

3031 Background: Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody conjugated to topoisomerase 1 inhibitor, deruxtecan, payload that is an effective treatment strategy across several tumor types and various HER2 expressions. The relative contributions of each of the underlying mechanisms driving the broad clinical activity require further elucidation for the ongoing rational development of this promising agent. To this end, our pilot study (NCT04294628) evaluates the pharmacodynamics (PD) of T-DXd in patients (pts) with solid tumors displaying a variety of HER2 expression levels. Methods: This multicenter pilot study enrolled pts with HER2-expressing advanced solid tumors as defined by HER2 immunohistochemistry (IHC) score of 1+ or greater or ERBB2 amplifications (amp) or mutations (mut). Baseline HER2 expression was evaluated by Ventana PATHWAY immunohistochemical (IHC) analysis. T-DXd was administered at 5.4 mg/kg intravenously once every 3 weeks, in 21-day cycles (C), with mandatory tumor biopsies collected at baseline, post-dose C1, and pre-dose C3. Blood samples for biomarker analyses were collected throughout the study. PD biomarkers for topoisomerase 1 (TOP1) target engagement, consequent DNA damage repair (DDR), and tumor immune microenvironment changes were analyzed. Overall response was also evaluated. Results: Sixty-one pts received T-DXd. Eligibility HER2 (eHER2) status was determined from pt records: 21 IHC 1+, 22 IHC 2+, 7 IHC 3+, 8 ERBB2 amp, 3 ERBB2 mut. Of the 41 pts with baseline biopsies centrally assessed for HER2 (bHER2) by IHC, 13 had bHER2 scores discordant with eHER2, including 8 patients who were eHER2 1-2+ but were bHER2 null. No new safety signals were observed. One pt had a complete response (cervical, bHER2 3+), 14 pts had confirmed partial responses (PR), including 3 who were bHER2 null (2 ovarian, 1 uterine), and 5 pts had unconfirmed PR (uPR). Of the 21 paired biopsies assessable for PD response, 15 demonstrated TOP1 target modulation and 14 of those 15 also demonstrated DDR induction. Substantial tumor infiltration and activation of CD8+ T cells at baseline and/or following T-DXd administration occurred in several patients and were particularly prevalent in those with response. In the one responding patient where lesion-specific analyses were possible, we observed significant diameter reduction (3.9 cm to 1.9 cm) and PD responses in a bHER2 null lesion. Conclusions: Clinical responses and target modulation were observed in pts irrespective of bHER2 expression. Lesion-specific analyses provide evidence of antitumor activity and target engagement even in a bHER2-null lesion. Genomic analyses to identify additional molecular determinants of response or resistance to T-DXd are ongoing. This project was funded in part by the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024. Clinical trial information: NCT04294628 .